US7807693B2ExpiredUtilityPatentIndex 41
Substituted prolinamides, manufacturing, and the use thereof as medicaments
Est. expiryMay 16, 2026(expired)· nominal 20-yr term from priority
Inventors:GERLACH KAIDAHMANN GEORGNAR HERBERTPFAU ROLANDPRIEPKE HENNINGSCHULER-METZ ANNETTEWIENEN WOLFGANG
A61P 43/00A61P 9/00A61P 7/02A61P 7/00A61P 25/16A61P 25/28C07D 401/14C07D 471/04C07D 401/12A61K 31/435
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Claims
Abstract
The present invention relates to new substituted prolinamides of general formula (I) wherein D, L, E, G, J, M, R 3 , R 4 , R 5 and R 13 are defined as in the specification, the tautomers, the enantiomers, the diastereomers, the mixtures, and the salts thereof.
Claims
exact text as granted — not AI-modified1. A compound of general formula (I)
wherein
D denotes a substituted bicyclic ring system of formula
wherein
K 1 denotes a —CH 2 , —CHR 7a , —CR 7b R 7c or a —C(O) group, and wherein R 7a /R 7b /R 7c each independently of one another denote a fluorine atom, a hydroxy, C 1-5 -alkyloxy, a C 1-5 -alkyl group, while the two groups R 7b /R 7c may not simultaneously be bound to the cyclic carbon atom via a heteroatom, except where —C(R 7b R 7c ) corresponds to a —CF 2 group, or two groups R 7b /R 7c together with the cyclic carbon atom may form a 3-membered carbocyclic group and
K 2 and K 3 each independently of one another denote a —CH 2 , —CHR 8a , —CR 8b R 8c or a —C(O)— group, wherein R 8a /R 8b /R 8c each independently of one another denote a C 1-5 -alkyl group, or two groups R 8b /R 8c together with the cyclic carbon atom may form a 3-membered saturated carbocyclic group
and
in all not more than four groups selected from among R 7a , R 7b , R 7c , R 8a , R 8b and R 8c may be present, and
X denotes an oxygen or sulphur atom, a sulphene, sulphone, —CF 2 — or an NR 1 group, wherein R 1 denotes a hydrogen atom or a hydroxy, C 1-3 -alkyloxy, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, a C 1-5 -alkyl, C 2-5 -alkenyl-CH 2 , C 2-5 -alkynyl-CH 2 or a C 3-6 -cycloalkyl group,
and wherein
A 1 denotes either N or CR 10
A 2 denotes either N or CR 11
A 3 denotes either N or CR 12
wherein R 10 , R 11 and R 12 each independently of one another denote a hydrogen, fluorine, chlorine, bromine or iodine atom, or a C 1-5 -alkyl, CF 3 , a cyano, carboxy, C 1-5 -alkyloxycarbonyl, hydroxy, C 1-3 -alkyloxy, CF 3 O, CHF 2 O, CH 2 FO, amino, C 1-5 -alkylamino, di-(C 1-5 -alkyl)-amino or C 4-7 -cycloalkyleneimino group, and
-L-E-G-J- denotes a C—C—C—C or —C—C═C—C group which may be substituted by R 4 and R 5 , and
R 3 denotes a hydrogen atom or a C 1-3 -alkyl group, and
R 4 denotes a hydrogen atom or a straight-chain or branched C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl group, wherein the hydrogen atoms of the methylene and/or methyl fragments of the straight-chain or branched C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl group may optionally be wholly or partly replaced by fluorine atoms, or wherein the hydrogen atoms of the methylene and/or methyl fragments of the straight-chain or branched C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl group may optionally each be substituted independently of one another by one to two substituents selected from among a C 3-5 -cycloalkyl group, a nitrile, hydroxy or C 1-5 -alkyloxy group, while the hydrogen atoms of the C 1-5 -alkyloxy group may optionally be wholly or partly replaced by fluorine atoms, an allyloxy, propargyloxy, benzyloxy, C 1-5 -alkylcarbonyloxy, C 1-5 -alkyloxycarbonyloxy, carboxy-C 1-5 -alkyloxy, C 1-5 -alkyloxycarbonyl-C 1-5 -alkyloxy, mercapto, C 1-5 -alkylsulphanyl, C 1-5 -alkylsulphinyl, C 1-5 -alkylsulphonyl, carboxy, C 1-5 -alkyloxycarbonyl, aminocarbonyl, C 1-5 -alkylaminocarbonyl, di-(C 1-5 -alkyl)-aminocarbonyl, C 4-7 -cycloalkyleneiminocarbonyl, aminosulphonyl, C 1-5 -alkylaminosulphonyl, di-(C 1-5 -alkyl)-aminosulphonyl, C 4-7 -cycloalkyleneiminosulphonyl, amino, C 1-5 -alkylamino, di-(C 1-5 -alkyl)-amino, C 1-5 -alkylcarbonylamino, C 1-5 -alkyl-sulphonylamino, N—(C 1-5 -alkylsulphonyl)-C 1-5 -alkylamino, C 3-6 -cycloalkylcarbonyl-amino group, or a morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl group, while the above-mentioned carbocyclic and heterocyclic groups in the ring may each be substituted by 1-4 C 1-3 -alkyl or C 1-3 -alkylcarbonyl groups or by 1-2 oxo groups, or wherein the hydrogen atoms of the sp 2 -hybridised carbon atoms of the straight-chain or branched C 2-6 -alkenyl group may optionally be wholly or partly replaced by fluorine atoms, or
R 4 denotes a nitrile, carboxy, aminocarbonyl, C 1-5 -alkylaminocarbonyl, C 3-6 -cycloalkylaminocarbonyl, di-(C 1-5 -alkyl)-aminocarbonyl, C 1-5 -alkyloxycarbonyl or a C 4-7 -cycloalkyleneiminocarbonyl group wherein optionally a methylene group may be replaced by a oxygen, sulphur or C 0-3 -alkyl-substituted nitrogen atom, or
R 4 denotes a phenyl, mono- or bicyclic heteroaryl, phenyl-C 1-5 -alkyl or mono- or bicyclic heteroaryl-C 1-5 -alkyl group, which may optionally be mono- to trisubstituted in the phenyl or heteroaryl moiety by identical or different substituents selected from among fluorine, chlorine, bromine and iodine atoms, and C 1-5 -alkyl, trifluoromethyl, amino, C 1-5 -alkyl-amino, di-(C 1-5 -alkyl)-amino, hydroxy, C 1-5 -alkyloxy, mono-, di- or trifluoromethoxy, carboxy and C 1-5 -alkyloxycarbonyl group,
and
if -L-E-G-J- denotes a —C—C—C—C group, R 4 at E or G may also denote a fluorine atom or a hydroxy, methoxy, C 3-5 -alkenyl-oxy, C 3-5 -alkynyloxy, C 2-5 -alkyloxy, C 3-6 -cycloalkyl-oxy, C 1-5 -alkylaminocarbonyloxy, di(C 1-5 -alkyl)aminocarbonyloxy or C 4-7 -cycloalkyleneiminocarbonyloxy, phenyl-C 0-3 -alkyloxy, heteroaryl-C 0-3 -alkyloxy, amino, C 1-5 -alkylamino, di-(C 1-5 -alkyl)-amino, C 4-7 -cycloalkyleneimino, C 1-3 -acylamino, (C 1-3 -acyl)C 1-3 -alkylamino, C 1-5 -alkyloxycarbonylamino, C 1-5 -alkylaminocarbonylamino, di(C 1-5 -alkyl)aminocarbonylamino or a C 4-7 -cycloalkyleneiminocarbonyl-amino group, while the methyl or methylene groups present in the above-mentioned alkyl or cycloalkyl groups may each independently of one another be substituted by a substituent selected from among morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, dimethylaminocarbonyl, C 1-5 -alkyloxycarbonyl, carboxy, methyl, hydroxy, methoxy or amino,
and
the above-mentioned phenyl or heteroaryl groups may optionally be mono- to trisubstituted by identical or different substituents selected from among fluorine, chlorine, bromine and iodine atoms, and C 1-5 -alkyl, trifluoromethyl, amino, C 1-5 -alkyl-amino, di-(C 1-5 -alkyl)-amino, hydroxy, C 1-5 -alkyloxy, mono-, di- or trifluoromethoxy, carboxy- and C 1-5 -alkyloxycarbonyl group,
with the proviso that two heteroatoms selected from among oxygen and nitrogen are separated from one another by precisely one optionally substituted CH 2 group or that two atoms form an —O—O or —S—O— bond is excluded, and
R 5 denotes a hydrogen atom, a C 1-5 alkyl, C 2-5 alkenyl or C 2-5 alkynyl or a phenyl-C 0-5 alkyl group, wherein the alkyl group may be substituted by a hydroxy, methoxy, hydroxycarbonyl or C 1-5 -alkoxycarbonyl group, or if R 5 is linked to E or G it may also denote a hydroxy or methoxy group, or
R 4 and R 5 , if they are bound to the same carbon atom, they may form together with the carbon atom a —C═O group or a —CF 2 — group, or
R 4 and R 5 , if they are bound to the same carbon atom or to two adjacent carbon atoms, together with the carbon atom(s) they may form a 3-7-membered carbocyclic group or a monounsaturated 5-7 membered carbocyclic group, wherein one of the carbon chain members of this cyclic group may be replaced by an oxygen or sulphur atom or a —NH, —N(C 1-5 -alkyl), —N(C 1-4 -alkylcarbonyl) or a carbonyl, sulphinyl or sulphonyl group, or two directly adjacent carbon chain members of these C 4-7 -carbocyclic groups may together be replaced by a —C(O)NH, —C(O)N(C 1-5 -alkyl), —S(O) 2 NH, or —S(O) 2 N(C 1-5 -alkyl) group, or four directly adjacent carbon chain members of these C 5-7 -carbocyclic groups may together be replaced by an —O—CH 2 —CH 2 —O group, or 1 to 3 carbon atoms of these 3-7-membered cyclic groups may optionally be substituted independently of one another by in each case one or two fluorine atoms or one or two C 1-5 -alkyl groups or a hydroxy, formyloxy, C 1-5 -alkyloxy, C 1-5 -alkylcarbonyloxy, amino, C 1-5 -alkylamino, di-(C 1-5 -alkyl)-amino, C 4-7 -cycloalkyleneimino, C 1-5 -alkylcarbonylamino, C 3-6 -cycloalkylcarbonylamino, nitrile, carboxy-C 1-5 -alkyl, C 1-5 -alkyloxycarbonyl-C 1-5 -alkyl, carboxy, C 1-5 -alkyloxycarbonyl, aminocarbonyl, C 1-5 -alkylaminocarbonyl, di-(C 1-5 -alkyl)-aminocarbonyl or C 4-7 -cycloalkyleneiminocarbonyl group, with the proviso that a cyclic group of this kind formed from R 4 and R 5 together, wherein two nitrogen atoms or one nitrogen and one oxygen atom in the cyclic group are separated from one another by precisely one optionally substituted CH 2 group, or wherein two atoms in the ring form a —O—-O or —S—O— bond is excluded,
or the fragment
denotes the group
R 13 denotes a hydrogen atom or a C 1-5 alkyl group,
M denotes a phenyl, thienyl or pyridyl ring optionally substituted by R 2 and R 6 , wherein
R 2 denotes a fluorine, chlorine, bromine or iodine atom or a methyl, ethyl, vinyl, methoxy, ethynyl, cyano or —C(O)NH 2 group, and
R 6 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom or a hydroxy, methoxy, trifluoromethoxy, a C 1-3 -alkyl optionally substituted by fluorine atoms, a cyano, amino or NH 2 C(O) group,
while, unless stated otherwise, by the term “heteroaryl group” mentioned hereinbefore in the definitions is meant a monocyclic 5- or 6-membered heteroaryl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms, and the 5-membered heteroaryl group contains an imino group optionally substituted by a C 1-3 -alkyl group, or an oxygen or sulphur atom, or an imino group optionally substituted by a C 1-3 -alkyl group or an oxygen or sulphur atom and additionally one or two nitrogen atoms, or an imino group optionally substituted by a C 1-3 -alkyl group and three nitrogen atoms, and moreover a phenyl ring optionally substituted by a fluorine, chlorine or bromine atom, a C 1-3 -alkyl, hydroxy, C 1-3 -alkyloxy group, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino or C 3-6 -cycloalkyleneimino group may be fused to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms, and the bond is effected via a nitrogen atom or a carbon atom of the heterocyclic moiety or a fused-on phenyl ring,
and wherein, unless stated otherwise, by the term “halogen atom” mentioned hereinbefore in the definitions is meant an atom selected from among fluorine, chlorine, bromine and iodine,
and wherein the alkyl, alkenyl, alkynyl and alkyloxy groups contained in the previously mentioned definitions which have more than two carbon atoms may, unless stated otherwise, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups may be identical or different,
and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions, unless stated otherwise, may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomers, the diastereomers, the mixtures, and the salts thereof.
2. The compound of general formula (I) according to claim 1 , wherein
X denotes an NR 1 group, wherein R 1 denotes a hydrogen atom or a C 1-5 -alkyl, allyl or cyclopropyl group, and
A 1 denotes CR 10 ,
A 2 denotes CR 11 ,
A 3 denotes either N or CR 12 ,
wherein R 10 , R 11 and R 12 each independently of one another denote a hydrogen, fluorine or chlorine atom, or a methyl, CF 3 , cyano, carboxy, C 1-5 -alkyloxycarbonyl, hydroxy, methoxy, CF 3 O, CHF 2 O, CH 2 FO group,
the tautomers, the enantiomers, the diastereomers, the mixtures, and the salts thereof.
3. The compound of general formula (I) according to claim 1 , wherein
R 4 denotes a hydrogen atom or a straight-chain or branched C 1-6 -alkyl group, wherein the hydrogen atoms of the methylene and/or methyl fragments of the straight-chain or branched C 1-6 -alkyl group may optionally be wholly or partly replaced by fluorine atoms, or wherein the hydrogen atoms of the methylene and/or methyl fragments of the straight-chain or branched C 1-6 -alkyl group may optionally each be substituted independently of one another by a substituent selected from among a hydroxy, C 1-5 -alkyloxy, carboxy, C 1-5 -alkyloxycarbonyl, aminocarbonyl, C 1-5 -alkylaminocarbonyl, di-(C 1-5 -alkyl)-aminocarbonyl, C 4-7 -cycloalkyleneiminocarbonyl, amino, C 1-5 -alkylamino, di-(C 1-5 -alkyl)-amino, C 1-5 -alkylcarbonylamino, C 1-5 -alkylsulphonylamino, N—(C 1-5 -alkylsulphonyl)-C 1-5 -alkylamino, C 3-6 -cycloalkylcarbonylamino group, or
R 4 denotes a nitrile, carboxy, aminocarbonyl, C 1-5 -alkylaminocarbonyl, C 3-6 -cycloalkylaminocarbonyl, di-(C 1-5 -alkyl)-aminocarbonyl, C 1-5 -alkyloxycarbonyl or a C 4-7 -cycloalkyleneiminocarbonyl group wherein a methylene group may optionally be replaced by a oxygen, sulphur or C 0-3 -alkyl-substituted nitrogen atom, and
if -L-E-G-J- denotes a —C—C—C—C group, R 4 at E or G may also denote a fluorine atom or a hydroxy, methoxy, C 3-5 -alkenyloxy, C 3-5 -alkynyloxy, C 2-5 -alkyl-oxy, C 3-6 -cycloalkyl-oxy, C 1-5 -alkylaminocarbonyloxy, di(C 1-5 -alkyl)aminocarbonyloxy or C 4-7 -cycloalkyleneiminocarbonyloxy, phenyl-C 0-2 -alkyloxy group, which may be substituted in the phenyl ring by 1-2 fluorine atoms or methoxy groups, an amino, C 1-5 -alkylamino, di-(C 1-5 -alkyl)-amino, C 4-7 -cycloalkyleneimino, C 1-3 -acylamino, (C 1-3 -acyl)C 1-3 -alkylamino, C 1-5 -alkyloxycarbonylamino, C 1-5 -alkylaminocarbonylamino, di(C 1-5 -alkyl)aminocarbonylamino or a C 4-7 -cycloalkyleneiminocarbonylamino group, while the methyl or methylene groups present in the above-mentioned alkyl or cycloalkyl groups may each independently of one another be substituted by a substituent selected from among dimethylaminocarbonyl, C 1-5 alkyloxycarbonyl, carboxy, methyl, hydroxy, methoxy or amino, with the proviso that two heteroatoms selected from among oxygen and nitrogen are separated from one another by precisely one optionally substituted CH 2 group, or that two atoms form an —O—O or —S—O— bond is excluded, and
R 5 denotes a hydrogen atom or a C 1-5 alkyl, allyl, propargyl or benzyl group, or if R 5 is linked to E or G, it may also denote a hydroxy or methoxy group or
R 4 and R 5 if they are bound to the same carbon atom, may form together with the carbon atom a —C═O group, or a —CF 2 — group, or
R 4 and R 5 if they are bound to the same carbon atom or to two adjacent carbon atoms, may form together with the carbon atom(s) a 3-7-membered carbocyclic group, while one of the carbon chain members of this cyclic group may be replaced by an oxygen or sulphur atom or a —NH, —N(C 1-5 -alkyl), —N(C 1-4 -alkylcarbonyl) or a carbonyl, sulphinyl or sulphonyl group, or two directly adjacent carbon chain members of these C 4-7 -carbocyclic groups may together be replaced by an —C(O)NH, —C(O)N(C 1-5 -alkyl), —S(O) 2 NH, or —S(O) 2 N(C 1-5 -alkyl) group, or four directly adjacent carbon chain members of these C 5-7 -carbocyclic groups may together be replaced by a —O—CH 2 —CH 2 O group, with the proviso that a cyclic group formed from R 4 and R 5 together, wherein two nitrogen atoms or one nitrogen and one oxygen atom in the cyclic group are separated from one another by precisely one optionally substituted CH 2 group, or wherein two atoms in the ring form a —O—O or —S—O— bond is excluded,
the tautomers, the enantiomers, the diastereomers, the mixtures, and the salts thereof.
4. The compound of general formula (I) according to claim 1 , wherein
-L-E-G-J- denotes a —C—C—C—C group that may be substituted by R 4 and R 5 , which are defined as in claim 1 ,
the tautomers, the enantiomers, the diastereomers, the mixtures, and the salts thereof.
5. The compound of general formula (I) according to claim 1 , wherein
D denotes a substituted bicyclic ring system of general formula
wherein
K 1 denotes a —CH 2 , —CHR 7a , —CR 7b R 7c or a —C(O) group, wherein R 7a denotes a C 1-2 -alkyl group and R 7b /R 7c each independently of one another denote a hydroxy, methoxy or a C 1-3 -alkyl group, while the two groups R 7b /R 7c may not simultaneously be bound to the cyclic carbon atom via an oxygen atom, or two groups R 7b /R 7c together with the cyclic carbon atom may form a 3-membered carbocyclic group,
and
K 2 and K 3 in each case independently of one another denote a —CH 2 , —CHR 8a or a —CR 8b R 8c group, wherein R 8a /R 8b /R 8c each independently of one another denote a C 1-3 -alkyl group, or two groups R 8b /R 8c together with the cyclic carbon atom may form a 3-membered saturated carbocyclic group, and in all not more than four groups selected from among R 7a , R 7b , R 7c , R 8a , R 8b and R 8c may be present, and
X denotes a NR 1 group, wherein
R 1 denotes a hydrogen atom or a C 1-3 -alkyl, allyl or cyclopropyl group, and
A 1 denotes CR 10 ,
A 2 denotes CR 11 ,
A 3 denotes CR 12 ,
wherein R 10 , R 11 and R 12 each independently of one another denote a hydrogen, fluorine or chlorine atom, or a methyl, CF 3 , hydroxy, methoxy, CF 3 O, CHF 2 O, CH 2 FO group,
and
-L-E-G-J- denotes a —C—C—C—C group, which may be substituted by R 4 and R 5 , and
R 3 denotes a hydrogen atom, and
R 4 denotes a hydrogen atom or a straight-chain or branched C 1-3 -alkyl group, wherein the hydrogen atoms of the methylene and/or methyl fragments of the straight-chain or branched C 1-6 -alkyl group may optionally be substituted independently of one another by a substituent selected from among a hydroxy, C 1-5 -alkyloxy, carboxy, C 1-5 -alkyloxycarbonyl group, or, if R 4 is bound to E or G, it may also denote a fluorine atom or a hydroxy, methoxy, C 3-5 -alkenyl-oxy, C 2-5 -alkyl-oxy, C 3-6 -cycloalkyl-oxy, C 1-5 -alkylaminocarbonyloxy, di(C 1-5 -alkyl)aminocarbonyloxy or C 4-7 -cycloalkyleneiminocarbonyloxy group, with the proviso that two heteroatoms selected from among oxygen and nitrogen are separated from one another by precisely one optionally substituted OH2 group is excluded, and
R 5 denotes a hydrogen atom or a C 1-5 alkyl, allyl or benzyl group, or if R 5 is linked to E or G it may also denote a hydroxy or methoxy group, or
R 4 and R 5 if they are bound to the same carbon atom, may form together with the carbon atom a —C═O group, or a —CF 2 — group, or
R 4 and R 5 if they are bound to the same carbon atom or to two adjacent carbon atoms, may form together with the carbon atom(s) a 3-6-membered carbocyclic group, while four directly adjacent carbon chain members of these C 5-6 -carbocyclic groups may together be replaced by an —O—CH 2 —CH 2 O group,
R 13 denotes a hydrogen atom,
M denotes a phenyl substituted by R 2 in the 4-position or a pyridyl ring substituted by R 2 in the 5-position, wherein R 2 denotes a fluorine, chlorine, bromine atom, a methoxy or ethynyl group, and
R 6 denotes a hydrogen or fluorine atom,
the tautomers, the enantiomers, the diastereomers, the mixtures, and the salts thereof.
6. The compound of general formula (I) according claim 1 , wherein the central ring
denotes either
the tautomers, the enantiomers, the diastereomers, the mixtures, and the salts thereof.
7. The compound of general formula (I) according to claim 1 , wherein
D denotes a substituted bicyclic ring system of general formula
the tautomers, the enantiomers, the diastereomers, the mixtures, and the salts thereof.
8. The compounds of general formula (I) according to claim 1 , which are in the R configuration at the chain members G and L of the 5-membered central ring, and the salts thereof.
9. A pharmaceutical composition comprising a compound according to claim 1 and one or more inert carriers or diluents.
10. A method for preparing a pharmaceutical composition comprises the step of formulating a compound according to claim 1 with one or more inert carrier or diluents.
11. A compound according to claim 1 , wherein said compound is selected from the group consisting of:
the tautomers, the enantiomers, the diastereomers, the mixtures and the salts thereof.
12. A compound according to claim 1 , wherein said compound is selected from the group consisting of:
the tautomers, the enantiomers, the diastereomers, the mixtures and the salts thereof.
13. A compound according to claim 1 , wherein said compound is selected from the group consisting of:
the tautomers, the enantiomers, the diastereomers, the mixtures and the salts thereof.
14. A compound according to claim 1 , wherein said compound is selected from the group consisting of:
the tautomers, the enantiomers, the diastereomers, the mixtures and the salts thereof.
15. A compound according to claim 1 , wherein said compound is selected from the group consisting of:
the tautomers, the enantiomers, the diastereomers, the mixtures and the salts thereof.Cited by (0)
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